Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH2:9][OH:10])=CC1C=CC=CC=1.[CH3:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH2:17])=[CH:14][CH:13]=1.CO>C1(C)C(C)=CC=CC=1>[CH3:9][O:10][CH:16]([C:15]1[CH:18]=[CH:19][C:12]([CH3:11])=[CH:13][CH:14]=1)[CH3:17]
Reactant: OCC=Cc1ccccc1
Reactant: C=Cc1ccc(C)cc1
Solvent: Cc1ccccc1C
Solvent: CO
Product: COC(C)c1ccc(C)cc1

Procedure:
The RPlug reactor model of ASPEN PLUS® (Ver. 7.1) is used to model the plug flow reactor (PFR) for the reaction of styrene (A8) with methanol to form the methanol styrene ether (MSE) (i.e. 1-methoxyethylbenzene). Laboratory rate data of the reaction in xylene solvent shows an empirical relationship that is directly proportional to styrene concentration and inversely proportional to methanol concentration. It considers the effect of methanol adsorption to account for an enhanced rate at low methanol concentrations, while also accounting for inhibition of methanol at very high methanol concentrations. The reaction model also takes into account the reverse reaction by including the equilibrium constant (Keqm) which is taken from the literature (Verevkin et. al., J. Chem. Eng. Data, 46, 984-990, 2001). The NRTL-RK property method is used for vapour-liquid equilibrium calculations. Binary interaction parameters were estimated for binary pairs involving MSE and for styrene-methanol. The reaction of 4-methylstyrene (A9) and methanol to form 1-(4-methylphenyl)ethyl methyl ether (4MMSE) is modeled as a side reaction. The reaction rate was estimated from conversion data found in the literature (Zhang and Corma, Royal Society of Chemistry, 2007, Chem. Commun. 2007, 3080-3082). Since both product components (MSE and 4MMSE) are not found in the ASPEN PLUS® database, Aspen Properties using the group contribution method of GANI were used to estimate boiling point temperatures and other critical constants. In this case, the reactor is designed as a constant temperature PFR operating at 100° C. It is sized for a 1 mol/h flow of styrene in a feed mixture containing 0.2433 mass fraction of styrene in xylene. An inert, unreactive C9H12 component present at 0.1957 mass fraction is included and modeled as 1-methyl-4-ethylbenzene. FIG. 5 is a schematic representation of a 1-stage plug flow reactor 402 for methanol styrene ether synthesis. The feed 406 contains styrene, methylstyrene and inert C8 and C9 compounds. Since Methanol to feed ratio in excess of the stoichiometric requirements are used, the effluent 410 from reactor 402 is sent to distillation column 107 to separate the methanol and unreacted feed compounds 409 from product ethers 136. Stream 409 is recycled and mixed with feed 406 and methanol stream 405. The mixture 407 then enters reactor 402.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[Li+].[OH-].O>C1COCC1.O.CO>[C:31]1([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([CH:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:25]3)[C:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[CH:8]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]=1
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C(=O)C(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(=O)N1CCC(N(c2cc(C3=CCCCC3)sc2C(=O)O)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 5-cyclohex-1-enyl-3-[(1-isobutyryl-piperidin-4-yl)-(trans-4-methyl cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (50 mg, 0.10 mmol) in THF:H2O:MeOH (3:1:2) (3 mL), was added LiOH in water (1N) (0.3 mL, 0.3 mmol). The reaction mixture was stirred at 70° C. for 5 h. The mixture was concentrated under reduced pressure on a rotary evaporator and the residue was treated with a solution of 0.1 N HCl and extracted in EtOAc. The EtOAc layer was dried over Na2SO4. Filtration and removal of the solvent under reduced pressure on a rotary evaporator followed by HPLC purification afforded 5-cyclohex-1-enyl-3-[(1-isobutyryl-piperidin-4-yl)-(trans-4-methyl cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (30.0 mg, 61%) as a foam.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:15][CH:14]2[C:16]([NH:18]/[N:19]=[CH:20]/[C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[CH:23]=[CH:24][N:25]=[CH:26]3)=[O:17])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[CH3:31]I>CN(C=O)C>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:15][CH:14]2[C:16]([N:18]([CH3:31])/[N:19]=[CH:20]/[C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[CH:23]=[CH:24][N:25]=[CH:26]3)=[O:17])=[CH:9][CH:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc(C2CC2C(=O)N/N=C/c2cccc3cnccc23)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(/N=C/c1cccc2cnccc12)C(=O)C1CC1c1ccc(C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.7 %

Procedure:
To a 0° C. suspension of NaH (16 mg, 0.6 mmol) in DMF (1 mL), (E)-2-(4-tert-butylphenyl)-N′-(isoquinolin-5-ylmethylene)cyclopropanecarbohydrazide (200 mg, 0.53 mmol) was added portionwise under nitrogen atmosphere. After being stirred for 1 h at 0° C., MeI (0.15 g, 1.0 mmol) was added and the reaction mixture stirred at RT for 1 h. The reaction mixture was then quenched with ice water and stirred for an additional 10 minutes. The precipitated solid was filtered and dried in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography using 20% ethyl acetate in hexanes to afford (E)-2-(4-tert-butylphenyl)-N′-(isoquinolin-5-ylmethylene)-N-methylcyclopropanecarbohydrazide (30 mg, 50%) as an off-white solid. 1H NMR (500 MHz, CDCl3): δ 9.24 (bs, 1 H), 8.50-8.41 (m, 1 H), 8.26-8.20 (m, 1 H), 8.02-7.94 (m, 2 H), 7.66-7.58 (m, 2 H), 7.39 (d, J=7.2 Hz, 2 H), 7.14 (d, J=7.2 Hz, 2 H), 3.28 (s, 3 H), 3.39-3.12 (m, 1 H), 2.63-2.56 (m, 1 H), 1.84-1.78 (m, 1 H), 1.49-1.38 (m, 1 H), 1.37 (s, 9 H). MS: M+H: m/z=386.2 and HPLC: 91%, (Condition-G).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][C:5]([CH3:12])=[CH:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]>CCOCC>[CH3:4][C:5]([CH3:12])=[CH:6][CH2:7][CH2:8][C:9]([O:11][CH3:3])=[O:10]
Reactant: C=[N+]=[N-]
Reactant: CC(C)=CCCC(=O)O
Solvent: CCOCC
Product: COC(=O)CCC=C(C)C
Temperature: 0 °C

Procedure:
Freshly prepared diazomethane in ether was added to an ice-cooled solution of 5-methyl-4-hexenoic acid (4.5 g, 35.16 mmol) in ether (10 mL) until the solution became slightly yellow in color. The solvent was then evaporated under vacuum to afford the title product as a colorless liquid in near quantitative yield (4.90 g). This product was used in the next reaction step without further purification. 1H NMR (CDCl3) δ1.62 & 1.68[2s, 6H, C(CH3)2], 2.30[m, 4H, (CH2)2], 3.69(s, 3H, COOCH3) and 5.07(t, 1H, CH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]2=[O:15])=[C:4]([CH3:16])[CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:16])[C:5]([C:9]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]=2[O:15][CH3:17])=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)cc(C)c1C1C(=O)CCC1=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC1=C(c2c(C)cc(Br)cc2C)C(=O)CC1
Temperature: 27.5 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(4-bromo-2,6-dimethylphenyl)cyclopentane-1,3-dione (40 g, 0.143 mol) in acetone (2000 ml) is added anhydrous potassium carbonate (98.5 g, 0.714 mol) and iodomethane (45 ml, 0.72 mol). The resulting mixture is stirred at 25-30°C. for 16 hours, then volatile solvents are removed in vacuo, and the residue is diluted with distilled water (200 ml) and extracted with ethyl acetate (3×500 ml). Organic fractions are combined, washed with distilled water, brine, then dried over sodium sulphate, filtered and the filtrate concentrated in vacuo. The crude product is purified by flash column chromatography to afford 2-(4-bromo-2,6-dimethylphenyl)-3-methoxycyclopent-2-enone.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]([CH:17]2[CH2:20][C:19](OC)([O:21]C)[CH2:18]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O.C(Cl)Cl>[C:1]([N:5]1[C:9]([NH:10][C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])=[CH:8][C:7]([CH:17]2[CH2:18][C:19](=[O:21])[CH2:20]2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC1(OC)CC(c2cc(NC(=O)C(F)(F)F)n(C(C)(C)C)n2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)n1nc(C2CC(=O)C2)cc1NC(=O)C(F)(F)F
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
To a stirring solution of N-[2-tert-butyl-5-(3,3-dimethoxy-cyclobutyl)-2H-pyrazol-3-yl]-2,2,2-trifluoro-acetamide (6.5 g, 18.5 mmol) in acetone (182 mL) and water (61 mL) was added p-toluenesulfonic acid monohydrate (1.8 g, 9.5 mmol) and the reaction mixture was heated to 65° C. After 1.5 hr, the reaction mixture was cooled to room temperature, diluted with CH2Cl2 (250 mL), and water (50 mL). The layers were separated and the aqueous layer was back-extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the resulting material was accomplished by trituration with isopropyl ether. The product was collected and dried under reduced pressure to yield the title compound (4.2 g, 76% yield, two crops) as a yellow solid. 400 MHz 1H NMR (CDCl3) d 7.86 (bs, 1H), 6.33 (s, 1H), 3.62 (dddd, J=7.6, 7.6, 7.6, 7.6 Hz, 1H), 3.46-3.30 (m, 4H), 1.62 (s, 9H). LRMS m/z (APCI+) 304 (M+1).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:19]3[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=3)=[N:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[NH:42]1[CH2:47][CH2:46][CH:45]([C:48]2[N:52]=[C:51]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=3)[NH:50][N:49]=2)[CH2:44][CH2:43]1.C(N(CC)CC)C.C(O)(=O)C>CN(C=O)C>[C:1]1([C:7]2[C:8]([C:19]3[CH:26]=[CH:25][C:22]([CH2:23][N:42]4[CH2:47][CH2:46][CH:45]([C:48]5[N:52]=[C:51]([C:53]6[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=6)[NH:50][N:49]=5)[CH2:44][CH2:43]4)=[CH:21][CH:20]=3)=[N:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2nc(C3CCNCC3)n[nH]2)nc1
Reactant: O=Cc1ccc(-c2nc(-c3ccccn3)ncc2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1ccc(-c2cnc(-c3ccccn3)nc2-c2ccc(CN3CCC(c4n[nH]c(-c5ccccn5)n4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-(5-Phenyl-2-pyridin-2-ylpyrimidin-4-yl)benzaldehyde (4-3; 0.011 g, 0.033 mmol), sodium triacetoxyborohydride (0.010 g, 0.049 mmol) and 2-(3-piperidin-4-yl-1H-1,2,4-triazol-5-yl)pyridine hydrochloride (0.022 g, 0.082 mmol) were stirred in 0.5 ml of anhydrous DMF. Triethylamine (0.014 ml, 0.098 mmol) and acetic acid (0.007 ml, 0.13 mmol) were added and the reaction was stirred at ambient temperature for 6 h. The reaction was quenched by the addition of 3 drops of water and the resulting solution was purified by reverse phase preparative chromatography. This afforded 5-phenyl-2-pyridin-2-yl-4-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)pyrimidine (4-4) as a trifluoroacetic acid salt. 1H NMR (CDCl3): δ 9.12 (s, 1H), 9.09 (d, 1H), 8.94 (d, 1H), 8.72 (d, 2H), 8.20 (m, 1H), 8.15 (m, 2H), 7.98 (s, 1H), 7.75 (d, 2H), 7.58 (m, 3H), 7.43 (m, 2H), 7.36 (m, 2H), 4.40 (s, 2H), 3.62 (m, 2H), 3.25 (m, 2H), 2.42 (m, 2H), 2.12 (m, 2H). m/z (m+1): 551.2
Reaction SMILES: [C:1](/[C:6](=[CH:11]/[C:12]1[CH:17]=[C:16](C(C)C)[CH:15]=[CH:14][C:13]=1[Br:21])/[CH2:7][C:8]([OH:10])=O)([O:3][CH2:4][CH3:5])=[O:2].O.[C:23]([O-])([O-])=O.[K+].[K+].[Na].C(O[C:34](=[O:36])[CH3:35])(=O)C>C(O)C>[CH2:4]([O:3][C:1]([C:6]1[CH:7]=[C:8]([OH:10])[C:17]2[C:12](=[C:13]([Br:21])[CH:14]=[CH:15][C:16]=2[O:36][CH:34]([CH3:23])[CH3:35])[CH:11]=1)=[O:2])[CH3:5]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)/C(=C/c1cc(C(C)C)ccc1Br)CC(=O)O
Agent: [K+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(O)c2c(OC(C)C)ccc(Br)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
12.9 g (34.8 mmol) (E)-3-carboethoxy-4-(2'-bromo-5'-isopropylphenyl)-3-butenic acid (3) were dissolved in 340 acetic anhydride and heated for 6 h in reflux. After cooling to room temperature, a solution of 200 g ice, 200 g water and 90 g K2CO3 were added. After extraction with dichloromethane, the combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The dried residue was dissolved in a solution of 8.40 g (389 mmol) sodium in 300 mL dry ethanol and stirred for 4 h at room temperature under Ar. The solvent was removed in vacuo and the residue was partitioned between 100 mL dichloromethane and 30 mL 2N HCl-solution. The organic phases were collected, dried (MgSO4) and concentrated under reduced pressure. The residue was recrystallized from isopropanol to give 11.7 g (95%) ethyl-8-bromo-4-hydroxy-5-isopropoxy-2-naphthoate as yellow crystals (m.p. 106° C.).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[C:20]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:23])[CH:21]=[CH2:22]>CN(C=O)C>[NH:9]([CH2:22][CH2:21][C:20]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:10]
Reactant: CC(C)(C)OC(=O)CN
Reactant: C=CC(=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of glycine t-butyl ester hydrochloride (20.7 g, 123 mmol) in DMF (50 mL) was added DIEA (21.5 mL, 123 mmol) and benzyl acrylate (20 g, 123 mmol). The mixture was allowed to stir at room temperature for 4 hours. This solution was concentrated in vacuo and the residue partitioned between saturated aqueous NaHCO3 and ethyl acetate and separated. The organic layer was washed once with saturated aqueous NaHCO3 and twice with brine. The ethyl acetate layer was dried (MgSO4), filtered and concentrated in vacuo to give 30 g (83%) of a slightly amber oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([CH2:12][CH2:13][CH2:14][C@H:15]([C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24]([CH2:25][C@@H:26]([OH:36])[CH2:27][CH2:28]2)=[CH:23][CH2:22]3)[CH2:19][CH2:18]1)[CH3:16])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN1CCCCC1=O.O>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][C@@H:10]([CH2:12][CH2:13][CH2:14][C@H:15]([C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH2:27][CH2:28]2)[CH2:23][CH2:22]3)[CH2:19][CH2:18]1)[CH3:16])[CH3:11])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H](CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CO[Si](C)(C)C(C)(C)C
Agent: CN1CCCCC1=O
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C)CO[Si](C)(C)C(C)(C)C
Yield: 85 %

Procedure:
A mixture of (25R)-26-(tert-butyldimethylsilyloxy)cholest-5-en-3β-ol (7.4g, 14.3mmol) and 1-methylpiperidone (55 mL) in toluene (550 mL) was heated to reflux temperature and 100ml toluene was distilled off. Aluminium triisopropyl oxide (15 g, 1377 mmol) was then added portionwise over 10 minutes and the whole heated at refux for 4 hours. After cooling, water (300 mL) was added and the aqueous layer separated and extracted with diethyl ether (5×100 mL). The combined organic layers were washed with water (2×60 mL), dried over magnesium sulphate and concentrated to give residue which was purified by flash chromatography to give 6.26 g (25R)-26-(tert-Butyldimethylsilyloxy)-cholest-4-en-3-one (6.26 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[CH3:27][C:28]1[CH:29]=[C:30]([N:34]=[C:35]=[O:36])[CH:31]=[CH:32][CH:33]=1>>[CH3:27][C:28]1[CH:29]=[C:30]([NH:34][C:35](=[O:36])[NH:1][CH2:2][C:3]([N:5]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:31]=[CH:32][CH:33]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1ccccc1Oc1ccccc1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2Oc2ccccc2)c1
Yield: 26.3 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with tert-butyl 2-[2-amino-N-(2-phenoxyphenyl)acetamido]acetate (4.7 g) and 3-methylphenyl isocyanate (1.9 g), and after recrystallisation in ethyl acetate, tert-butyl 2-{2-[3-(3-methylphenyl)ureido]-N-(2-phenoxyphenyl)acetamido}acetate (1.7 g), m.p. 204° C., is obtained.
Reaction SMILES: [C:1]([O:9]C)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:11](O)(=O)C>O>[C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:9])[CH3:11]
Reactant: COC(=O)c1cccnc1
Reactant: CC(=O)O
Solvent: O
Product: CC(=O)c1cccnc1

Procedure:
A mixture of 29 g/h of methyl nicotinate, 76 g/h of acetic acid and 26 g/h of water was evaporated in an evaporator and passed, together with 10 l/h of nitrogen, at 420° C., over 150 ml of a catalyst which contained 2% by weight of sodium oxide, the remainder being anatase. The reaction gases were then cooled and were collected in a receiver. From the discharged two-phase mixture, the organic phase was analyzed by gas chromatography. The conversion of nicotinic ester and of acetic acid was 100% in each case. The selectivity with respect to 3-acetylpyridine was 54%. In addition, pyridine was formed with a selectivity of 41%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1.I[CH3:26]>CCO>[CH3:26][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Reactant: CI
Solvent: CCO
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCN(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.7 %

Procedure:
To a solution of 2-[1-(piperidin-3-yl)-ethylamino]-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 18) (20.9 mg, 0.065 mmol) in EtOH (0.6 mL) was added iodomethane (40 μL, 0.65 mmol). The mixture was placed in an oil bath at 60° C. and heated for 4 h, then stirred at room temperature overnight. The solvent was removed under reduced pressure, and the crude product was purified by preparative thin layer chromatography (1:9 2M NH3 in MeOH:CH2Cl2) to obtain 4.1 mg of the title compound. Partial 1H NMR (500 MHz, CDCl3): δ 8.61 (s, 1H); 8.35 (br s, 1H); 8.16 (d, J=7.5 Hz, 1H); 7.84 (d, J=7.1 Hz, 1H); 7.37 (m, 2H); 6.75 (d, J=5.5 Hz, 1H); 4.12 (m, 1H); 2.92 (d, J=9 Hz, 1H); 2.8 (d, J=11 Hz, 1H); 2.27 (s, 3H); 1.26 (d, J=6.7 Hz, 3H). Mass spectrum 337.3 (ESI, M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])=[O:11])=[CH:4][C:3]=1[OH:21].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29](F)[CH:30]=1)[C:26]#[N:27].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:21][C:3]2[CH:4]=[C:5]([CH2:8][N:9]3[C:10](=[O:11])[C:12]4[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:14]3=[O:15])[CH:6]=[CH:7][C:2]=2[Cl:1])[CH:30]=1)[C:26]#[N:27]
Reactant: N#Cc1cc(F)cc(Cl)c1
Reactant: O=C(O)c1ccccc1C(=O)NCc1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: N#Cc1cc(Cl)cc(Oc2cc(CN3C(=O)c4ccccc4C3=O)ccc2Cl)c1
Yield: 22.7 %

Procedure:
3-Chloro-5-({2-chloro-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}oxy)benzonitrile was prepared in a in a similar manner as described herein from 2-({[(4-chloro-3-hydroxyphenyl)methyl]amino}carbonyl)benzoic acid (3.0 g, 10.4 mmol), 3-chloro-5-fluorobenzonitrile (2.5 g, 15.6 mmol), K2CO3 (4.3 g, 31.0 mmol) and NMP (25.0 mL). Purification was accomplished by column chromatography (hexane/EtOAc) to afford the title compound (1.0 g, 24%) as a solid.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[NH:4][C:5](=[O:19])[C:6]2[NH:11][C:10]([NH2:12])=[C:9]([CH2:13][C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[C:7]=2[N:8]=1.Cl.[N:21]([O-])=O.[Na+]>O>[Cl-:1].[NH2:2][C:3]1[NH:4][C:5](=[O:19])[C:6]2[NH:11][C:10]([N+:12]#[N:21])=[C:9]([CH2:13][C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[C:7]=2[N:8]=1
Reactant: Nc1nc2c(Cc3ccsc3)c(N)[nH]c2c(=O)[nH]1
Reactant: Cl
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#[N+]c1[nH]c2c(=O)[nH]c(N)nc2c1Cc1ccsc1
Product: [Cl-]
Temperature: 0 °C
Reaction time: 1.3 h

Procedure:
Charged 23.4 kg (74.1 mol) of 2,6-diamino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3,2-d]pyrimidin-4-one, hydrochloride, monohydrate (U.S. Pat. No. 4,923,872), 240 L water and 14.9 kg (147.1 mol) 36% hydrochloric acid to a nitrogen-purged 800 L reactor. The resulting slurry is cooled to 0° C. A solution of 7.9 kg (114.5 mol) sodium nitrite in 20 L water is added to the slurry over 40 minutes. The reaction mixture is heated to 20° C. and held at that temperature for 1.3 hours. The product is collected and washed with 90 n water yielding 63.5 kg of the title compound as a water wet cake.
Reaction SMILES: [C:1]([C:4]1[C:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])[CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:24])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+].O1CCCC1>CO.C(#N)C>[NH2:31][CH:1]([C:4]1[C:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])[CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:24])[CH:5]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CCC(=O)N[C@H]1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CO
Product: CCC(=O)N[C@H]1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)C1
Temperature: 65 °C

Procedure:
A mixture of N-[(3S)-1-(7-acetyl-5-chloroquinolin-8-yl)pyrrolidin-3-yl]propanamide (0.011 g, 0.032 mmol) and ammonium acetate (0.0245 g, 0.318 mmol) in methanol (0.15 mL) and acetonitrile (0.15 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.080 mL, 0.080 mmol). The reaction was heated at 65° C. overnight, then cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic phase were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C18H24ClN4O (M+H)+: m/z=347.2; Found: 347.1.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C1Nc2ccc(F)cc2Oc2sc3c(c21)CCCC3
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CN1CCN(C2=Nc3ccc(F)cc3Oc3sc4c(c32)CCCC4)CC1

Procedure:
In the same manner as in Example 80 and using 8-fluoro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 8-fluoro-1,2,3,4-tetrahydro-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzoxazepine is obtained. STARTING MATERIAL SNYTHESIS EXAMPLE 66